Transcriptional regulation of nephrin gene by peroxisome proliferator-activated receptor-γ agonist:: Molecular mechanism of the antiproteinuric effect of pioglitazone
Transcriptional regulation of nephrin gene by peroxisome proliferator-activated receptor-γ agonist:: Molecular mechanism of the antiproteinuric effect of pioglitazone
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DOI：
10.1681/asn.2005090983
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发表时间：
2006-06-01
影响因子：
13.6
通讯作者：
Remuzzi, Giuseppe
中科院分区：
文献类型：
--
作者：
Benigni, Ariela;Zoja, Carla;Remuzzi, Giuseppe
在进行性肾病、被动性Heymann肾炎（PHN）免疫模型中，探索了过氧化物酶体增殖物激活受体-γ（PPAR-gamma）激动剂吡格列酮的肾保护潜力，并与作为肾保护标准治疗的血管紧张素II受体拮抗剂进行了比较。PHN大鼠从第2个月至第8个月经口接受溶媒、吡格列酮（10 mg/kg，每日两次）或坎地沙坦（1 mg/kg，每日两次）。吡格列酮与坎地沙坦一样有效地减少蛋白尿，并限制肾功能和结构变化。未治疗PHN大鼠的肾脏显示出较低的nephrin mRNA和蛋白质比对照组，都恢复了吡格列酮。在病程的早期和晚期都可以看到这种影响。吡格列酮的抗蛋白尿作用是否可能是由于其对nephrin基因转录的影响也进行了研究。HK-2细胞用质粒转染，所述质粒在含有推定的过氧化物酶体增殖物应答元件（PPRE）的人nephrin基因启动子的部分（2-kb或325-bp）下携带荧光素酶基因，并与吡格列酮（10 μ M）孵育。吡格列酮可显著提高荧光素酶基因的转录活性，其中325 bp片段的表达最强。双酚A二缩水甘油醚（一种PPAR-gamma合成拮抗剂）可以阻止荧光素酶活性的增加。电泳迁移率变动分析实验表明，直接相互作用的过氧化物酶体增殖物激活受体/类维生素A X受体异源二聚体PPRE存在于nephrin启动子的增强子区域。总之，吡格列酮在免疫介导的肾小球肾炎中发挥与血管紧张素II受体拮抗剂相同的抗蛋白尿作用。通过启动子中特异性PPRE增强nephrin基因转录揭示了PPAR-gamma激动剂肾脏保护的新机制。
The renoprotective potential of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist pioglitazone was explored in an immune model of progressive nephropathy, passive Heymann nephritis (PHN), compared with that of an angiotensin II receptor antagonist, taken as standard therapy for renoprotection. PHN rats received orally vehicle, pioglitazone (10 mg/kg twice daily), or candesartan (1 mg/kg twice daily) from months 2 to 8. Piciglitazone reduced proteinuria as effectively as candesartan and limited renal functional and structural changes. Kidneys from untreated PHN rats showed lower nephrin mRNA and protein than controls, both restored by pioglitazone. The effect was seen both early and late during the course of the disease. Whether the antiproteinuric effect of pioglitazone could be due to its effect on nephrin gene transcription also was investigated. HK-2 cells were transfected with plasmids that harbor the luciferase gene under portions (2-kb or 325-bp) of human nephrin gene promoter that contain putative peroxisome proliferator-responsive elements (PPRE) and incubated with pioglitazone (10 mu M). Transcriptional activity of luciferase gene was highly increased by pioglitazone, with the strongest expression achieved with the 325-bp fragment. Increase in luciferase activity was prevented by bisphenol A diglycidyl ether, a PPAR-gamma synthetic antagonist. Electrophoretic mobility shift assay experiments showed a direct interaction of PPAR/retinoid X receptor heterodimers to PPRE present in the enhancer region of the nephrin promoter. In conclusion, pioglitazone exerts an antiproteinuric effect in immune-mediated glomerulonephritis as angiotensin II receptor antagonist does. Enhancement of nephrin gene transcription through specific PPRE in its promoter discloses a novel mechanism of renoprotection for PPAR-gamma agonists.